Blood, 15 May 2003, Vol. 101, No. 10, pp. 3761-3761
Sickle cell mouse models are hot!
The development of ingenious mouse models of sickle cell
disease by variable loss or removal of mouse globin genes and
transgenic introduction of human 
and 
S
and/or S-Antilles globin genes has profoundly
improved the opportunities to understand the complex pathophysiology of
the sickling disorders as well as to develop new therapies. It is
vital, however, to validate these models by comparison to human sickle
disorders. This is especially important for nonhemoglobin abnormalities
that may both reflect and contribute to the chronic hemolysis, vascular occlusion, and organ damage so characteristic of these disorders. Thus,
the study by Belcher and colleagues (page 3953) is very important
because it demonstrates variable increases in markers of systemic
inflammation in 4 different mouse models of sickle cell anemia. Among
their findings are variable elevations in leukocyte counts, serum
amyloid P-component levels (an acute phase protein related to
C-reactive protein), and IL-6 levels. Animals also demonstrated
evidence of large and small blood vessel endothelial activation, with
increased lung VCAM, ICAM, and PECAM-1, as well as increased expression
of lung nuclear factor kappa B (NF-
B). Because humans with
sickle cell disease demonstrate similar evidence of variably increased
markers of systemic inflammation, these data help to validate the mouse
models. Moreover, because leukocytosis in humans with sickle cell
disease is a risk factor for disease severity and stroke, and because
leukocytes and activated endothelial cells have been implicated in
contributing to vascular occlusion, additional studies of these models
are likely to provide both new insights into the pathophysiology of
sickle cell disease, including the processes that link the hemoglobin
abnormality to the inflammatory response, and opportunities to test
novel therapeutic interventions.
Barry S. Coller
Rockefeller
University
